Rebecca F. Boettger

High Cumulative Dose Exposure to Voriconazole is Associated with Cutaneous Squamous Cell Carcinoma in Lung Transplant Recipients

BACKGROUND Lung transplant recipients (LTR) have an increased risk of cutaneous squamous cell carcinoma (SCC) due to immunosuppressive therapy. Voriconazole, which is associated with phototoxic side effects in some patients, may be an additional risk factor for SCC in this population. METHODS To test whether voriconazole is a risk factor for developing SCC in LTR, we evaluated cumulative exposure to voriconazole in 327 adults who underwent lung transplantation at one center between 1991 and 2010. Voriconazole exposure was assessed as a time-varying covariate. We used survival analysis methods to assess the risk of developing SCC over time. RESULTS Exposure to voriconazole was associated with a 2.6-fold increased risk for SCC. This phenomenon was dose-dependent: the risk for SCC increased by 5.6% with each 60-day exposure at a standard dose of 200 mg twice daily. At 5 years after transplant, voriconazole conferred an absolute risk increase for SCC of 28%. CONCLUSIONS These results suggest that caution should be taken when using voriconazole in LTR because this drug increases the already high risk for SCC in this population.

Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients.

Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but it has been associated with an increased risk of developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance the competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco, who were transplanted between October 1991 and December 2012 (n = 455) to investigate whether voriconazole exposure affected development of SCC, Aspergillus colonization, invasive aspergillosis and all‐cause mortality. Voriconazole exposure was associated with a 73% increased risk of developing SCC (hazard ratio [HR] 1.73; 95% confidence interval [CI]: 1.04–2.88; p = 0.03), with each additional 30‐day exposure at the standard dose increasing the risk by 3.0% (HR 1.03; 95% CI: 1.02–1.04; p < 0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR 0.50; 95% CI: 0.34–0.72; p < 0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all‐cause mortality among subjects who developed Aspergillus colonization (HR 0.34; 95% CI: 0.13–0.91; p = 0.03) but had no significant impact on those without colonization. Physicians should consider patient‐specific factors that modify the potential risks and benefits of voriconazole for the care of lung transplant recipients.

Use of sublingual tacrolimus in lung transplant recipients

BACKGROUND In lung transplant recipients (LTRs), tacrolimus is often utilized as a core component of immunosuppressive regimens. Although tacrolimus can be delivered orally or intravenously, oral tacrolimus is associated with fewer adverse effects. Various reports have suggested that sublingual tacrolimus may be used as an alternative to oral tacrolimus; however, information regarding converting between routes is limited. We aimed to identify a dose conversion ratio between oral and sublingual tacrolimus in LTRs. METHODS We identified adult LTRs at the University of California, San Francisco, who transitioned between oral and sublingual tacrolimus between 2005 and 2010 (n = 34). For tacrolimus, we obtained steady-state blood concentrations and total daily doses before and after the route conversion. Blood concentrations divided by daily doses were calculated for each route. The conversion ratio was then defined as: (blood concentration(sublingual)/daily dose(sublingual))/(blood concentration(oral)/daily dose(oral)). This ratio was tested in inpatient vs outpatient settings and in the presence of impaired gastric emptying. Adverse effects, including nephrotoxicity, hepatotoxicity and anaphylaxis, were evaluated. RESULTS The conversion ratio of sublingual to oral tacrolimus was 0.46 ± 0.20 (mean ± SD). The ratio was not associated with hospital setting (p = 0.82) or with impaired gastric emptying (p = 0.31). When comparing sublingual to oral tacrolimus administration, there were no differences in serum creatinine, liver function tests or anaphylaxis. CONCLUSIONS Tacrolimus administered sublingually at approximately half of the oral dose achieves therapeutic blood concentrations and is safe in LTRs. Delivery via the sublingual route using this conversion ratio may aid clinicians in maintaining therapeutic tacrolimus blood concentrations while avoiding the need for intravenous administration.